Substantial progress has been recently made in understanding how massive numbers of B lymphocytes are made daily within mammalian bone marrow. A number of differentiation events have been identified which occur during the last several days of this process. Distinctive surface markers can be used to isolate and characterize cells during this period and we already know of several soluble mediators which influence their replication and maturation. Additional information of this kind should be forthcoming in the near future and we plan to employ several new methods and approaches to phenotyping such late B lineage precursors. However, the most important and least understood issues relate to earlier events and relevant studies are planned using genetically defective mice, long term culture methodology and a variety of lympho-hemopoietic growth and differentiation factors. The progeny of multipotential stem cells simultaneously progress through eight separate lineages while closely packed within the hemopoietic cords of bone marrow. It is important to learn how these are coordinately regulated and how defects in one lineage influence events in others. A comprehensive study will be done of various progenitor cells in a number of experimental animal models and hypotheses will be tested about cells which might have critical regulatory roles. It is now practical to investigate functional relationships between adherent stromal cells and B lineage lymphocytes which depend on them for growth in long term culture. Soluble mediators as well as short range communication may be involved. In addition, adhesion molecules must be important for appropriate sorting and migration of differentiating cells within bone marrow. It should be possible to characterize ones which mediate recognition between lymphocyte progenitors and microenvironmental cells in culture and determine if this process is affected by genetically determined defects.